title: Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine.
abstract: An enzymatic study was performed to clarify the mechanism of 18 acute deaths in patients who had received the new oral antiviral drug, sorivudine (SRV), during anticancer chemotherapy with 5-fluorouracil (5-FU) prodrugs. Human dihydropyrimidine dehydrogenase (hDPD), playing a key role in the liver as the rate-limiting enzyme in catabolism of 5-FU, was expressed in E. coli, purified and incubated in the presence of NADPH with SRV or (E)-5-(2-bromovinyl)uracil (BVU), a metabolite of SRV produced by human gut flora. hDPD was rapidly and irreversibly inactivated by BVU, but not by SRV. Radioactivity of [14C]BVU was incorporated into hDPD in the presence of NADPH in a manner reciprocal to the enzyme inactivation. In the absence of NADPH, hDPD was not inactivated by BVU, nor radiolabeled with [14C]BVU. Thus, as we demonstrated previously with studies using the rat, the acute deaths were strongly suggested to be attributable to markedly elevated tissue 5-FU levels which were responsible for irreversible inhibition of hDPD by covalent binding of a reduced form of BVU as a suicide inactivator.
authors.affiliation: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ogura
authors.forename: T
authors.initials: T
authors.lastname: Nishiyama
authors.forename: H
authors.initials: H
authors.lastname: Takubo
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.forename: H
authors.initials: H
authors.lastname: Okuda
authors.forename: K
authors.initials: K
authors.lastname: Arakawa
authors.forename: M
authors.initials: M
authors.lastname: Fukushima
authors.forename: S
authors.initials: S
authors.lastname: Nagayama
authors.forename: Y
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: T
authors.initials: T
authors.lastname: Watabe
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism; D001976:Bromouracil / Q000031:analogs & derivatives* / Q000633:toxicity; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D001086:Arabinofuranosyluracil; D001976:Bromouracil; C046140:5-(2-bromovinyl)uracil; C031368:sorivudine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)